Inclusion Criteria - Phase 2 Part
1. Subjects of respective country's legal age or older at the time of written informed
consent.
2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or
metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I,
II, or III types.
3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity
sufficient to allow for local lab analysis of HER1 and HER2 expression status. If
archived tumor tissue is not available, subject must agree to undergo fresh core
biopsy to obtain adequate tumor tissue
4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or
+++) and HER-2 (at level of +, or ++) using standard criteria in the local lab.
Subjects with HER-2 over expression at level of +++ determined by IHC and subject
confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has
contradiction to trastuzumab*.
*For details of contraindication related to trastuzumab, refer to package insert or US
treatment guideline.
5. Have radiographically measurable disease as defined by RECIST v1.1
6. Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
7. Estimated life expectancy of more than 4 months
8. Able to swallow and retain oral medication
9. Subject with adequate organ and hematological function:
d) Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L
ii. Platelet count ≥ 100 x 109/L iii. HgB≥9 g/dL (packed red cell blood transfusions
are not allowed within one week prior to baseline hematology profile).
e) Renal functions, as follows: i. Serum creatinine ≤1.5x upper limit of normal (ULN)
or estimated glomerular filtration rate (eGFR)> 60 mL/min/1.73m2 f) Hepatic function,
as follows: i. Total bilirubin ≤1.5 x ULN ii. AST and ALT ≤2.5 x ULN (or ≤5 x ULN in
subjects with liver metastasis) iii. Albumin ≥25 g/L
10. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7
days prior to randomization for premenopausal women of reproductive capacity and for
women 12 months after menopause
11. Willingness to use highly effective birth control method (failure rate <1%) while on
study.
Inclusion Criteria - Phase 3 Part
1. Subjects of respective country's legal age or older at the time of written informed
consent.
2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or
metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I,
II, or III types.
3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity
sufficient to allow for local lab analysis of HER1 and HER2 expression status. If
archived tumor tissue is not available, subject must agree to undergo fresh core
biopsy to obtain adequate tumor tissue.
4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or
+++) and HER-2 (at level of +, or ++) using standard criteria in the local lab.
Subjects with HER-2 over expression at level of +++ determined by IHC and subject
confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has
contradiction to trastuzumab*.
5. Note: *For details of contraindication related to trastuzumab, refer to package insert
or US treatment guideline
6. Subjects with ECOG performance status of 0 to 1
7. Able to swallow and retain oral medication
8. Subject with adequate organ and hematological function:
a) Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L
ii. Platelet count ≥100 x 109/L iii. HgB≥9 g/dL (packed red cell blood transfusions
are not allowed within one week prior to baseline hematology profile).
b) Renal functions, as follows: i. Serum creatinine ≤ 1.5x ULN or eGFR> 60
mL/min/1.73m2 c) Hepatic function, as follows: i. Total bilirubin ≤1.5 x ULN ii. AST
and ALT ≤2.5 x ULN (or ≤5 x ULN in subjects with liver metastasis) iii. Albumin ≥25
g/L
9. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7
days prior to randomization for premenopausal women of reproductive capacity and for
women 12 months after menopause
10. Willingness to use highly effective birth control method (failure rate <1%) while on
study.
Exclusion Criteria:
1. Subject with HER-2 over expression at level of +++ determined by IHC or subject
confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by Fluorescence in
situ hybridization (FISH) in the central lab.
2. Prior systemic anti-cancer treatment for inoperable locally advanced, recurrent, or
metastatic adenocarcinoma of the stomach or GEJ. However, previous neo adjuvant
chemotherapy is allowed if subject has progression of disease more than 6 months after
neoadjuvant treatment.
3. Subjects have undergone major surgery within 28 days prior to randomization
4. Subject with brain lesion, known brain metastases (unless previously treated and well
controlled for a period of at least 4weeks).
5. Subject with malabsorption syndrome, diseases significantly affecting gastrointestinal
function, extensive resection of the stomach or small bowel, or difficulty in
swallowing and retaining oral medications.
6. Subjects with an uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, New York heart Association class III or IV congestive
heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia,
diabetes, hypertension, or psychiatric illness/social situations that would limit
compliance with study requirements.
7. Subjects with any history of other malignancy unless in remission for more than 1
year. (Nonmelanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with
curative intent is not exclusionary).
8. Female subjects who are pregnant or breast feeding.
9. Subjects who were previously treated with varlitinib.
10. Subjects who took other investigational drugs and/or used investigational medical
devices or have undergone major surgery within 28 days before initiating varlitinib
therapy.
11. Are currently on or have received anti-cancer therapy, radiation or local treatment
within the past 28 days
12. Subject with unresolved or unstable serious toxicity (≥ CTCAE 4.03 Grade 2) from prior
administration of another investigational drug and/or prior cancer treatment(excluding
hair loss)
13. Subjects with a known history of human immunodeficiency virus (HIV), decompensated
cirrhosis, hepatitis B infection with hepatitis B virus DNA exceeding 2000 IU/mL or
hepatitis C (treatment naïve or after treatment without sustained virologic response).
14. Known history of drug addiction within the past 1 year.
15. Subjects who need continuous treatment with proton pump inhibitors during the study
period.
16. Any history or presence of clinically significant cardiovascular, respiratory,
hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,
neurologic or psychiatric disease or any other condition which in the opinion of the
Investigator could jeopardize the safety of the subject or the validity of the study
results.
